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Huntingtin and the control of long distance transport of synaptic / extrasynaptic signals in health and disease

亨廷顿蛋白以及健康和疾病中突触/突触外信号长距离传输的控制

基本信息

批准号：
258728186
负责人：
Dr. Michael R. Kreutz
金额：
--
依托单位：
Forschungsgruppe Neuroplastizität
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/258728186?language=en
关键词：
Huntingtin control long distance transport

项目摘要

Huntingtin (HTT) the protein that when mutated causes Huntingtons disease (HD), a devastating neurological disorder acts as a scaffold for protein complexes with an emerging role in the transport of vesicles and proteins in axons and dendrites. HTT interacts with the molecular motors dynein and kinesin to regulate the efficacy and the directionality of transport placing HTT at the center of functional nodes that regulate the transport of signals over long distances in axons and dendrites. At an early stage of the disease no structural damage exists but rather an impairment of synaptic function that manifests in a shift from synaptic to extrasynaptic N-Methyl-D-Aspartate-receptor (NMDAR) signalling. Jacob is a synapto-nuclear protein messenger that encodes and transduces the synaptic or extra-synaptic origin of NMDAR signals to the nucleus and that plays a role in regulation of gene expression either leading to cell death or promoting cell survival and synaptic plasticity. Nuclear trafficking of Jacob requires an active importin- and dynein- mediated retrograde transport along microtubuli. Several studies have provided compelling evidence that huntingtin interacts with proteins which are involved in gene transcription, cell signaling and intracellular transport. Very recent reports suggest that huntingtin might provide a platform that links transcriptional regulators to molecular motors for transport from synapse to nucleus. With this proposal we will address this idea. We will also investigate whether perturbation of microtubule-based transport contributes to impairments in long-distance signalling in HD. More specifically we propose that HTT and Jacob could play a major role in integrating long-range signals from the synapse to the nucleus and consequently will modify gene expression in health and in HD. We assume that a functional interplay between Jacob, a protein that can dock an NMDAR-derived signalosome to nuclear target sites and mutant HTT might contribute to neurodegeneration in HD. We will test whether HTT and Jacob interact directly and we aim to determine the molecular identity of the signals transported to the nucleus in normal and HD conditions with special emphasis on non-vesicular transport of transcriptional regulators. Most important we want to assess whether extrasynaptic NMDAR trigger nuclear import of Jacob in HD and how this relates to cell death and neurodegeneration. Taken together the proposed work program will shed new light on the physiological function of HTT, which has been neglected and at the same time we will learn how the investigated mechanisms impacts on the pathophysiology of the disease.

亨廷顿蛋白（HTT）是一种蛋白质，当突变时会导致亨廷顿病（HD），这是一种毁灭性的神经系统疾病，可作为蛋白质复合物的支架，在轴突和树突中转运囊泡和蛋白质方面发挥新的作用。HTT与分子马达动力蛋白和驱动蛋白相互作用以调节转运的功效和方向性，将HTT置于功能节点的中心，所述功能节点调节轴突和树突中长距离的信号转运。在疾病的早期阶段，不存在结构损伤，而是突触功能受损，其表现为从突触到突触外N-甲基-D-天冬氨酸受体（NMDAR）信号传导的转变。Jacob是一种突触核蛋白信使，其编码和转导NMDAR信号的突触或突触外起源至细胞核，并且在基因表达的调节中起作用，导致细胞死亡或促进细胞存活和突触可塑性。Jacob的核运输需要主动的输入蛋白和动力蛋白介导的沿着微管的逆行运输。一些研究提供了令人信服的证据表明，亨廷顿蛋白与参与基因转录、细胞信号传导和细胞内转运的蛋白质相互作用。最近的报告表明，亨廷顿蛋白可能提供了一个平台，将转录调节因子与分子马达联系起来，以便从突触运输到细胞核。我们将通过这一提议来解决这一问题。我们还将调查是否微管为基础的运输扰动有助于损害在HD的长距离信号。更具体地说，我们认为HTT和Jacob可能在整合从突触到细胞核的长程信号方面发挥重要作用，因此将改变健康和HD中的基因表达。我们假设Jacob（一种可以将NMDAR衍生的信号体停靠在核靶位点的蛋白质）和突变HTT之间的功能相互作用可能有助于HD中的神经变性。我们将测试HTT和雅各布是否直接相互作用，我们的目标是确定在正常和HD条件下转运到细胞核的信号的分子身份，特别强调转录调节因子的非囊泡转运。最重要的是，我们想评估突触外NMDAR是否触发HD中Jacob的核输入，以及这与细胞死亡和神经变性的关系。总之，拟议的工作计划将揭示HTT的生理功能，这一直被忽视，同时我们将了解所研究的机制如何影响疾病的病理生理学。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuronal DNA Methyltransferases: Epigenetic Mediators between Synaptic Activity and Gene Expression?

DOI：
10.1177/1073858417707457
发表时间：
2018-04
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
0
作者：
Bayraktar G;Kreutz MR
通讯作者：
Kreutz MR

A Dendritic Golgi Satellite between ERGIC and Retromer.